Effect of wheel-running during abstinence on subsequent nicotine-seeking in rats

Rationale

Exercise appears to be a promising non-pharmacological treatment for nicotine addiction that may be useful for the vulnerable adolescent population.

Objectives

The aim of this study is to determine if wheel-running, an animal model of aerobic exercise, during an abstinence period would decrease subsequent nicotine-seeking in rats that had extended access to nicotine self-administration during adolescence.

Methods

Male adolescent rats (n?=?55) were trained to self-administer saline or nicotine infusions (5 or 10 μg/kg) under a fixed ratio 1 schedule with a maximum of 20 infusions/day beginning on postnatal day 30. After 5 days, access was extended to 23 h/day with unlimited infusions for a total of 10 days. After the last self-administration session, rats were moved to polycarbonate cages for a 10-day abstinence period where they either had access to a locked or unlocked running wheel for 2 h/day. Nicotine-seeking was examined following the 10th day of abstinence under a within-session extinction/cue-induced reinstatement paradigm.

Results

Intake was higher at the 10 μg/kg dose as compared to the 5 μg/kg dose; however, intake did not differ within doses prior to wheel assignment. Compared to saline controls, rats that self-administered nicotine at either dose showed a significant increase in drug-seeking during extinction, and consistent with our hypothesis, exercise during abstinence attenuated this effect. Nicotine led to modest but significant levels of cue-induced reinstatement; however, in this adolescent-onset model, levels were variable and not affected by exercise.

Conclusions

Exercise may effectively reduce relapse vulnerability for adolescent-onset nicotine addiction     

The effects of varied extinction procedures on contingent cue-induced reinstatement in Sprague-Dawley rats

Rationale

Cue exposure therapy, which attempts to limit relapse by reducing reactivity to cocaine-paired cues through repeated exposures, has had limited success.

Objectives

The current experiments examined cocaine cue-induced anxiogenesis and investigated whether a model of cue exposure therapy would reduce reinstatement of cocaine seeking in rats with a history of cocaine self-administration.

Methods

Male rats experienced daily intravenous cocaine self-administration. Rats then experienced exposure to either the self-administration context or the context plus noncontingent presentations of cocaine-paired cues. Immediately following exposure, anxiety-like behavior was measured using elevated plus maze and defensive burying tests. In a second group of rats, self-administration was followed by 7 days of exposure to the context, context + noncontingent cue exposure, lever extinction, or cue + lever extinction. All animals then underwent two contingent cue-induced reinstatement tests separated by 7 days of lever extinction.

Results

Exposure to noncontingent cocaine-paired cues in the self-administration context increased anxiety-like behavior on the defensive burying test. Animals that experienced lever + cue extinction displayed the least cocaine seeking on the first reinstatement test, and lever extinction reduced cocaine seeking below context exposure or context + noncontingent cue exposure. All animals had similar levels of cocaine seeking on the second reinstatement test.

Conclusion

Noncontingent cue exposure causes anxiety, and noncontingent cue and context exposure are less effective at reducing contingent cue-induced reinstatement than lever or lever + cue extinction. These data indicate that active extinction of the drug-taking response may be critical for reduction of relapse proclivity in former cocaine users.     

Facilitation of intravenous nicotine self-administration in rats by a motivationally neutral sensory stimulus

Rationale and objective

Intravenous infusions of nicotine appear to exert little primary reinforcing effects in adult rats but, instead, maintain self-administration behavior at least, in part, by increasing the intrinsic reinforcing effects of drug-paired sensory stimuli. The present study examined instead the impact of a motivationally neutral cue on self-administration.

Methods

Adult male Long-Evans rats were permitted to self-administer nicotine (0.015 mg/kg IV given over 30 s, 2 h/day) or saline presented with or without a sensory stimulus (light, white noise). Fixed and progressive ratio reinforcement schedules of nicotine reinforcement were tested. Experiment 2 determined whether noncontingent nicotine or mecamylamine (nicotinic antagonist) would induce lever pressing for either sensory stimulus. Experiment 3 tested whether the white noise stimulus alone could maintain responding after repeated pairing with self-administered nicotine. Finally, the sensory stimuli were assessed for possible aversive properties.

Results

Nicotine infusions alone were at best weakly reinforcing. The white noise stimulus, presented alone, was neither reinforcing nor aversive, whereas the white light appeared marginally reinforcing. Both stimuli, however, facilitated intravenous nicotine self-administration. Neither nicotine nor mecamylamine challenge rendered the white noise reinforcing. The white noise, after being self-administered with nicotine, failed to maintain self-administration behavior on its own.

Conclusions

Even a motivationally neutral sensory stimulus, lacking detectable primary or secondary reinforcing properties, can facilitate self-administration of nicotine. Possibly, drug-paired stimuli provide a "response marker" or serve as a temporal bridge between the operant response and drug effect. Motivationally neutral stimuli may therefore serve to isolate primary reinforcing effects of nicotine.     

Age influences the effects of nicotine and monoamine oxidase inhibition on mood-related behaviors in rats

Rationale

Epidemiological studies have demonstrated a comorbidity of smoking with depression and anxiety, particularly during adolescence. However, few animal studies have considered possible synergistic interactions between nicotine and other tobacco smoke constituents, such as monoamine oxidase (MAO) inhibitors, in the regulation of mood.

Objectives

The aim of the study was to test the hypothesis that nicotine combined with the irreversible MAO inhibitor, tranylcypromine, will differentially affect depression- and anxiety-related behaviors in adolescent and adult rats.

Methods

Nicotine (0, 0.05, 0.2 mg/kg, s.c.) and tranylcypromine (3 mg/kg, i.p.) were tested separately, or together, on male rats aged postnatal days 30 and 68, in three mood-related behavioral tests: forced swim test (FST), elevated plus maze (EPM), and open field.

Results

Nicotine (0.2 mg/kg) in adults significantly decreased floating time in the FST and increased time spent in the open arm of the EPM, with no change in locomotor activity. Tranylcypromine pretreatment combined with nicotine (0.2 mg/kg) significantly increased locomotor activity and time spent in the center of the open field. Whereas nicotine alone had no significant effect on adolescents, it significantly increased locomotor activity and decreased floating time in the FST when combined with tranylcypromine pretreatment.

Conclusions

There is an age-dependent effect of nicotine, alone and in combination with MAO inhibition, on mood-related behaviors. Whereas nicotine alone induces mood improvement in adults, it has no effect on adolescents. Nicotine combined with tranylcypromine has unique, age-dependent effects. Thus, experimental studies of smoking should consider both age and other tobacco constituents, such as MAO inhibitors, as critical factors.     

Effects of the combination of metyrapone and oxazepam on intravenous nicotine self-administration in rats

Rationale

Despite increased education regarding its dangers, cigarette smoking remains a significant public health concern due to serious associated health consequences such as cancer and respiratory and cardiovascular diseases. Most smokers fail in their attempts to quit smoking, and current pharmacological interventions have relatively low levels of efficacy and are associated with significant adverse events. We have previously reported that combinations of metyrapone and oxazepam, administered at doses that were ineffective when delivered singly, resulted in dose-related decreases in cocaine self-administration in rats while not affecting food-maintained responding during the same sessions.

Objectives

The current study was designed to test the effects of the administration of a metyrapone:oxazepam combination on nicotine self-administration in rats.

Methods

Several dose combinations of metyrapone (12.5, 25 or 50 mg/kg) and oxazepam (5 or 10 mg/kg) were tested in rats trained to intravenously (IV) self-administer nicotine (0.03 mg/kg/infusion) during 1-h self-administration sessions using both fixed-ratio and progressive-ratio (PR) schedules of reinforcement.

Results

The administration of low doses of metyrapone and oxazepam in combination significantly decreased IV nicotine self-administration in rats. At the lowest doses of 12.5 mg/kg of metyrapone and 5 mg/kg of oxazepam, the drugs alone did not decrease IV nicotine self-administration, but the combination was effective. Varenicline was also tested using the fixed-ratio schedule, and reductions in nicotine intake were similar to those seen with the moderate dose of the combination.

Conclusions

The results of this study suggest a potential utility of the combination of metyrapone and oxazepam for smoking cessation in humans.     

Effects of combined exercise and progesterone treatments on cocaine seeking in male and female rats

Background

Individually, both treatment with progesterone and concurrent access to an exercise wheel reduce cocaine self-administration under long-access conditions and suppress cocaine-primed reinstatement in female rats. In the present study, wheel running and progesterone (alone and combined) were assessed for their effects on reinstatement of cocaine-seeking primed by yohimbine, cocaine, and cocaine-paired cues.

Methods

Male and female rats were implanted with an intravenous catheter and allowed to self-administer cocaine (0.4 mg/kg/inf, iv) during 6-h sessions for 10 days. Subsequently, the groups of male and female rats were each divided into two groups that were given concurrent access to either a locked or unlocked running wheel under extinction conditions for 14 days. Next, all four groups were tested in a within-subjects design for reinstatement of cocaine-seeking precipitated by separate administration of cocaine-paired stimuli, yohimbine, or cocaine or the combination of yohimbine?+?cocaine-paired stimuli or cocaine?+?cocaine-paired stimuli. These priming conditions were tested in the presence of concurrent wheel access (W), pretreatment with progesterone (P), or both (W?+?P).

Results

In agreement with previous results, females responded more for cocaine than males during maintenance. Additionally, concurrent wheel running attenuated extinction responses and cocaine-primed reinstatement in females but not in males. Across all priming conditions, W?+?P reduced reinstatement compared to control conditions, and for cocaine-primed reinstatement in male rats, the combined W?+?P treatment was more effective than W or P alone.

Conclusion

Under certain conditions, combined behavioral (exercise) and pharmacological (progesterone) interventions were more successful at reducing cocaine-seeking behavior than either intervention alone.     

Treatment of cocaine withdrawal anxiety with guanfacine: relationships to cocaine intake and reinstatement of cocaine seeking in rats

Rationale

Successful treatment of cocaine addiction is severely impeded by the propensity of users to relapse. Withdrawal severity may serve as a key predictor of susceptibility to relapse. Therefore, the identification and treatment of cocaine withdrawal symptoms such as anxiety may improve addiction treatment outcome.

Objectives

The current study examined the role of anxiety-like behavior during cocaine withdrawal and anxiolytic treatment in reinstatement of cocaine seeking in an animal model of relapse.

Methods

Male rats experienced daily IV cocaine self-administration. One group of animals received the norepinephrine α-2 agonist, guanfacine, or vehicle prior to anxiety testing 48 h after the last self-administration session. In the second group of rats, relationships between cocaine intake, anxiety-like behavior after withdrawal of cocaine, and reinstatement responding were investigated. The third and fourth groups of animals received guanfacine, yohimbine (norepinephrine α-2 antagonist), or vehicle once per day for 3 days 48 h after cessation of cocaine self-administration, followed by extinction and subsequent reinstatement induced by cocaine injections, cocaine-paired cues, and yohimbine administration.

Results

Cocaine-withdrawn rats at 48 h demonstrated higher levels of anxiety-like behavior as measured on a defensive burying task when compared to yoked saline controls, an effect reversed by guanfacine treatment. Cocaine intake was positively correlated with measures of anxiety-like behavior during early withdrawal, and this anxiety-like behavior was significantly correlated with subsequent cocaine-primed reinstatement. Yohimbine treatment during early withdrawal increased reinstatement to conditioned cues, while guanfacine treatment reduced reinstatement to yohimbine.

Conclusions

These studies suggest an important role for noradrenergic mediation of anxiety-like behavior that emerges after withdrawal of cocaine and potential risk of relapse as modeled by reinstatement, and suggest that treatment of anxiety symptoms during early abstinence may reduce the risk of relapse.     

Exaggerated cue-induced reinstatement of cocaine seeking but not incubation of cocaine craving in a developmental rat model of schizophrenia

Rationale

Patients with schizophrenia exhibit high comorbidity for substance abuse, but the biological underpinnings of this dual-diagnosis condition are still unclear. Previous studies have shown that rats with a neonatal ventral hippocampal lesion (NVHL), a widely used developmental animal model of schizophrenia, exhibit increased cocaine and methamphetamine self-administration and cocaine-induced reinstatement.

Objective

Here, we assessed whether a NVHL would also potentiate cue-induced reinstatement of cocaine seeking and the time-dependent increases in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving) in adult rats.

Methods

Rats were trained to self-administer cocaine (3 or 6 h/day with 0.75 mg?kg^?1?infusion^?1 paired with a tone-light cue) for 10 days, followed by extinction training (3 h/day) and cue-induced reinstatement of cocaine seeking. Other rats were tested for incubation of cocaine craving, assessed in extinction tests 1 and 30 days after the last self-administration session.

Results

Although there was no significant difference in cocaine intake between NVHL and sham controls, NVHL rats took significantly longer to reach an a priori set extinction criterion and exhibited enhanced cue-induced reinstatement. However, while cue-induced cocaine seeking was higher after 30 days than after 1 day of withdrawal (incubation of cocaine craving), the NVHL had no effect on this incubation.

Conclusion

These data confirm previous reports on enhanced resistance to extinction after NVHL and demonstrate that NVHL rats exhibit enhanced cue-induced reinstatement of cocaine seeking after extinction, a measure of drug relapse.     

Sex differences in the effect of wheel running on subsequent nicotine-seeking in a rat adolescent-onset self-administration model

Rationale

Wheel running attenuates nicotine-seeking in male adolescent rats; however, it is not known if this effect extends to females.

Objective

To determine if wheel running during abstinence would differentially attenuate subsequent nicotine-seeking in male and female rats that had extended access to nicotine self-administration during adolescence.

Methods

Male (n?=?49) and female (n?=?43) adolescent rats self-administered saline or nicotine (5 μg/kg) under an extended access (23-h) paradigm. Following the last self-administration session, rats were moved to polycarbonate cages for an abstinence period where they either had access to a locked or unlocked running wheel for 2 h/day. Subsequently, nicotine-seeking was examined under a within-session extinction/cue-induced reinstatement paradigm. Due to low levels of nicotine-seeking in females in both wheel groups, additional groups were included that were housed without access to a running wheel during abstinence.

Results

Females self-administered more nicotine as compared to males; however, within males and females, intake did not differ between groups prior to wheel assignment. Compared to saline controls, males and females that self-administered nicotine showed a significant increase in drug-seeking during extinction. Wheel running during abstinence attenuated nicotine-seeking during extinction in males. In females, access to either locked or unlocked wheels attenuated nicotine-seeking during extinction. While responding was reinstated by cues in both males and females, levels were modest and not significantly affected by exercise in this adolescent-onset model.

Conclusions

While wheel running reduced subsequent nicotine-seeking in males, access to a wheel, either locked or unlocked, was sufficient to suppress nicotine-seeking in females.     

The effects of the novel DA D3 receptor antagonist SR 21502 on cocaine reward, cocaine seeking and cocaine-induced locomotor activity in rats

Rationale

There is a focus on developing D3 receptor antagonists as cocaine addiction treatments.

Objective

We investigated the effects of a novel selective D3 receptor antagonist, SR 21502, on cocaine reward, cocaine-seeking, food reward, spontaneous locomotor activity and cocaine-induced locomotor activity in rats.

Methods

In Experiment 1, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement and tested with vehicle or one of three doses of SR 21502. In Experiment 2, animals were trained to self-administer cocaine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with vehicle or one of the SR 21502 doses on cue-induced reinstatement of responding. In Experiment 3, animals were trained to lever press for food under a PR schedule and tested with vehicle or one dose of the compound. In Experiments 4 and 5, in separate groups of animals, the vehicle and three doses of SR 21502 were tested on spontaneous or cocaine (10 mg/kg, IP)-induced locomotor activity, respectively.

Results

SR 21502 produced significant, dose-related (3.75, 7.5 and 15 mg/kg) reductions in breakpoint for cocaine self-administration, cue-induced reinstatement (3.75, 7.5 and 15 mg/kg) and cocaine-induced locomotor activity (3.75, 7.5 and 15 mg/kg) but failed to reduce food self-administration and spontaneous locomotor activity.

Conclusions

SR 21502 decreases cocaine reward, cocaine-seeking and locomotor activity at doses that have no effect on food reward or spontaneous locomotor activity. These data suggest SR 21502 may selectively inhibit cocaine’s rewarding, incentive motivational and stimulant effects.     

The stereotypy-inducing effects of N-substituted benztropine analogs alone and in combination with cocaine do not account for their blockade of cocaine self-administration

Rationale

Previous studies have demonstrated that several N-substituted 4′, 4″-diF-benztropine (BZT) analogs with high dopamine transporter affinity selectively decreased cocaine self-administration without affecting food-maintained behavior in rats.

Objectives

The present study examined if the decreases in cocaine self-administration are due to competition from excess behavioral activity (hyperlocomotion or stereotypy) induced by the BZT analogs alone or in combination with cocaine.

Results

Pretreatments with the typical dopamine uptake inhibitor methylphenidate [1.0, 3.2, and 10 mg/kg, intraperitoneally (i.p.)] dose-dependently shifted the cocaine self-administration dose–effect curve (0, 0.032, 0.1, 0.32, and 1.0 mg/kg/injection) leftward. The shift in the dose–effect curve was obtained at doses of methylphenidate that, when administered alone, also decreased food-maintained behavior and increased locomotor activity and stereotypy. In contrast, the N-substituted BZT analogs, JHW 007 (1.0, 3.2, and 10 mg/kg, i.p.), AHN 1-055 (10 mg/kg), and, AHN 2-005 (10 mg/kg), as previously reported, decreased the maximum for the cocaine self-administration dose–effect curve, and did so at doses that were virtually without effects on food-maintained behavior. Further, the BZT analogs alone had minimal effects on locomotor activity and stereotypies and did not appreciably change the effects of cocaine on these measures when administered in combination with cocaine.

Conclusions

The present results suggest that the decrease in cocaine self-administration produced by the N-substituted BZT analogs is due to an antagonism of the reinforcing effects of cocaine rather than due to interference from competing behavioral overstimulation, and further supports the development of N-substituted BZT analogs as medications to treat cocaine abuse.     

The relationship between cocaine self-administration and actigraphy-based measures of sleep in adult rhesus monkeys

Rationale

Clinical trials show that chronic cocaine users suffer from sleep disturbances and preclinical research has shown that acute sleep deprivation increases the rate of cocaine self-administration in rats.

Objective

This study examined the effect of cocaine self-administration on behavioral indices of sleep and alternatively the effect of sleep disruption on cocaine-maintained responding by rhesus monkeys.

Methods

Seven adult rhesus monkeys, fitted with Actical® activity monitors, were trained to respond under a concurrent choice paradigm with food (three 1.0-g pellets) and cocaine (0.003–0.3 mg/kg) or saline presentation. For each monkey, the lowest preferred dose of cocaine (>80 % cocaine choice) was determined. Activity data were analyzed during lights out (2000-0600) to determine sleep efficiency, sleep latency, and total activity counts. Subsequently, the monkeys’ sleep was disrupted (every hour during lights-out period) the night prior to food–cocaine choice sessions.

Results

Self-administration of the preferred dose of cocaine resulted in a significant decrease in sleep efficiency, with a significant increase in total lights-out activity. Sleep disruption significantly altered behavioral indices of sleep, similar to those seen following cocaine self-administration. However, sleep disruption did not affect cocaine self-administration under concurrent choice conditions.

Conclusions

Based on these findings, cocaine self-administration does appear to disrupt behavioral indices of sleep, although it remains to be determined if treatments that improve sleep measures can affect future cocaine taking.     

Drugs of abuse as memory modulators: a study of cocaine in rats

Rationale

It has been proposed that drugs of abuse reinforce behavior partly, or wholly, because they facilitate learning by enhancing memory consolidation. Cocaine can clearly serve as a reinforcer, but its effect on learning has not been fully characterized.

Objectives

To explore the effects of different regimens of pre- and post-training cocaine administration on win-stay and object learning.

Methods

Cocaine naïve and cocaine pre-exposed (30 mg/kg/day, ×5 days followed by 7 days drug-free) male Sprague-Dawley rats received cocaine (0, 1, 2.5, 7.5, or 20 mg/kg, i.p.) immediately following training on a win-stay task in a radial maze or following the sample phase of an object learning task. Win-stay performance was also assessed in tests of extinction and after a set shift.

Results

Post-training cocaine did not improve accuracy on the win-stay task and produced performance deficits at 20 mg/kg. These deficits were attenuated by prior cocaine exposure. There was indirect evidence of facilitated learning in extinction and set shift tests, but the effective dosage was different (2.5 and 7.5 mg/kg, respectively). Post-training cocaine produced dose-dependent improvements in object learning.

Conclusion

Post-training cocaine administration can facilitate learning, but this effect is highly dependent on the dose and the type of task employed.     

Peer influences on drug self-administration: Social facilitation and social inhibition of cocaine intake in male rats

Rationale

One problem facing animal models of intravenous drug self-administration, particularly those examining social manipulations, is that subjects must be removed from the home environment and separated from cagemates during testing. This represents a limitation of animal models because it fails to capture the complex social environments in which drug use often occur.

Objectives

The aim of this study was to examine intravenous cocaine self-administration in isolated and socially housed rats, with the caveat that the socially housed subjects lived together 24 h/day, including during daily self-administration sessions. As a secondary aim, the study examined the impact of a companion that also self-administered cocaine versus a companion without access to cocaine.

Methods

Male rats were obtained at weaning and reared in isolated or pair-housed conditions for 6 weeks. Rats were then implanted with intravenous catheters and transferred to custom-built operant conditioning chambers that served as home cages for the remainder of the study. For some socially housed subjects, both rats had simultaneous access to cocaine; for others, only one rat of the pair had access to cocaine.

Results

Cocaine self-administration was facilitated in socially housed rats if both members of the pair had access to cocaine; however, cocaine self-administration was inhibited if only one rat of the pair had access to cocaine.

Conclusions

These data indicate that the self-administration behavior of a peer, not merely the presence of a peer, determines whether cocaine self-administration is facilitated or inhibited by social contact.     

Substituted heteroaromatic compounds: effect on nicotine self-administration in rats

Rationale

Certain compounds that nonselectively inhibit a prominent human nicotine-metabolizing enzyme (i.e., human cytochrome P-450 2A6, hCYP 2A6) showed inhibition of smoking in humans. However, a comprehensive examination of hCYP 2A6 inhibitors to decrease nicotine self-administration in rats has not been reported.

Objectives

We tested substituted heteroaromatic compounds designed to selectively inhibit hCYP 2A6 in a model system to (a) examine selective hCYP 2A6 inhibitors to decrease cotinine formation in vivo in rats administered with nicotine and (b) examine their efficacy to decrease nicotine self-administration in rats.

Methods

Rats were trained to IV self-administer nicotine in 1-h sessions. Nicotine self-administration was carried out at a unit dose of 0.03?mg/kg/infusion in 0.1?ml/s. Pretreatment with substituted heteroaromatic test compounds (0.5–25?mg/kg, i.p., 30?min prior to nicotine self-administration sessions) resulted in dose-dependent decreases of nicotine self-administration. Using operant conditioning techniques, nicotine- vs. food-reinforced responding was evaluated for compounds 10 and 11.

Results

Compounds 10 and 11 selectively decreased nicotine self-administration with estimated ED₅₀ values 4 and 2.8?mg/kg, respectively. Of the test compounds examined, none showed significant affinity for mammalian α4β2- or α7-neuronal nicotinic acetylcholine (nAChR) receptors and none were inhibitors of the human dopamine transporter (hDAT); thus, neither the endogenous nAChRs nor DAT apparently plays a role in decreasing nicotine self-administration for this series of compounds.

Conclusion

The results indicate that chemical analogs of nicotine can play a role in nicotine self-administration harm reduction but a non-nAChR and a non-hDAT mechanism are likely involved.     

Tobacco smoke exposure induces nicotine dependence in rats

Rationale

Tobacco smoke contains nicotine and many other compounds that act in concert on the brain reward system. Therefore, animal models are needed that allow the investigation of chronic exposure to the full spectrum of tobacco smoke constituents.

Objectives

The aim of these studies was to investigate if exposure to tobacco smoke leads to nicotine dependence in rats.

Methods

The intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Somatic signs were recorded from a checklist of nicotine abstinence signs. Nicotine self-administration sessions were conducted to investigate if tobacco smoke exposure affects the motivation to self-administer nicotine. Nicotinic receptor autoradiography was used to investigate if exposure to tobacco smoke affects central α7 nicotinic acetylcholine receptor (nAChR) and non-α7 nAChR levels (primarily α4β2 nAChRs).

Results

The nAChR antagonist mecamylamine dose-dependently elevated the brain reward thresholds of the rats exposed to tobacco smoke and did not affect the brain reward thresholds of the untreated control rats. Furthermore, mecamylamine induced more somatic withdrawal signs in the smoke-exposed rats than in the control rats. Nicotine self-administration was decreased 1 day after the last tobacco smoke exposure sessions and was returned to control levels 5 days later. Tobacco smoke exposure increased the α7 nAChR density in the CA2/3 area and the stratum oriens and increased the non-α7 nAChR density in the dentate gyrus.

Conclusion

Tobacco smoke exposure leads to nicotine dependence as indicated by precipitated affective and somatic withdrawal signs and induces an upregulation of nAChRs in the hippocampus.     

Disrupted social development enhances the motivation for cocaine in rats

Rationale

Early social experiences are of major importance for behavioural development. In particular, social play behaviour during post-weaning development is thought to facilitate the attainment of social, emotional and cognitive capacities. Conversely, social insults during development can cause long-lasting behavioural impairments and increase the vulnerability for psychiatric disorders, such as drug addiction.

Objectives

The aim of this study was to investigate whether a lack of social experiences during the juvenile and early adolescent stage, when social play behaviour is highly abundant, alters cocaine self-administration in rats.

Methods

Rats were socially isolated from postnatal days 21 to 42 followed by re-socialization until adulthood. Cocaine self-administration was then assessed under a fixed ratio and progressive ratio schedule of reinforcement. Next, cue, cocaine and stress-induced reinstatement of cocaine seeking was determined following extinction of self-administration.

Results

Early social isolation resulted in an enhanced acquisition of self-administration of a low dose (0.083 mg/infusion) of cocaine, but the sensitivity to cocaine reinforcement, assessed using a dose–response analysis, was not altered in isolated rats. Moreover, isolated rats displayed an increased motivation for cocaine under a progressive ratio schedule of reinforcement. Extinction and reinstatement of cocaine seeking was not affected by early social isolation.

Conclusions

Early social isolation causes a long-lasting increase in the motivation to self-administer cocaine. Thus, aberrations in post-weaning social development, such as the absence of social play, enhance the vulnerability for drug addiction later in life.     

Effects of stressors on the reinforcing efficacy of nicotine in adolescent and adult rats

Rationale and objectives

Stress increases drug intake. This depends on the stressor, drug, and aspect of drug seeking assessed. The objectives of these experiments done in adolescent and adult male rats were to (1) examine social defeat effects on acquisition of nicotine self-administration (SA) and the reinforcing efficacy of nicotine and (2) determine the effects of acute exposure to intermittent footshock (FS) or yohimbine on the reinforcing efficacy of nicotine.

Methods

In experiment 1, rats received four defeat exposures prior to nicotine SA acquisition and progressive ratio (PR) SA sessions (30 μg/kg nicotine/infusion). Exposure to an olfactory cue previously paired with defeat was also tested on responding maintained by nicotine on the PR schedule. In experiments 2 and 3, the effects of FS (5 and 10 min) or yohimbine (0.625 and 1.25 mg/kg, i.p.) on PR responding for nicotine (15, 30, or 60 μg/kg/infusion) were assessed. Adolescents were aged PD34-36 and adults PD81-85 at the beginning of nicotine SA training.

Results

Defeat did not affect nicotine SA acquisition. Prior exposure to defeat or a defeat-paired olfactory cue did not affect PR responding for nicotine. FS modestly decreased PR responding in adolescents at the middle nicotine infusion dose. Yohimbine increased PR responding independent of nicotine infusion dose and age.

Conclusions

Together with previous work with other drugs, our data indicate that the effects of stress on the reinforcing efficacy of nicotine are stressor- and drug-dependent. This suggests that there is heterogeneity among stressors on how they affect neuronal systems underlying drug intake.     

Hypothalamic Neuropeptide S receptor blockade decreases discriminative cue-induced reinstatement of cocaine seeking in the rat

Rationale

Previous studies have shown that activation of brain neuropeptide S receptor (NPSR) facilitates reinstatement of cocaine seeking elicited by environmental cues predictive of drug availability. This finding suggests the possibility that blockade of NPSR receptors may be of therapeutic benefit in cocaine addiction. To evaluate this hypothesis, we investigated the effect of two newly synthetized NPSR antagonists, namely the quinolinone-amide derivative NPSR-QA1 and the NPS peptidic analogue [D-Cys(tBu)⁵]NPS on cocaine self-administration and on discriminative cue-induced relapse to cocaine seeking in the rat.

Methods

Separate groups of rats self-administered food and cocaine 0.25 mg/kg/inf in FR1 and FR5 (fixed ratio reinforcement schedules) for 30-min and 2-h sessions per day. After food and cocaine intake reached baseline levels, the effect of NPSR-QA1 was tested on cocaine and food self-administration. The NPSR-QA1 was injected intraperitoneally and its effect on discriminative cue-induced reinstatement was evaluated, while [D-Cys(tBut)⁵]NPS was injected intracranially, intra-lateral hypothalamus, intra-perifornical area of the hypothalamus, and intra-central amygdala. The effect of the NPSR-QA1 on extinction of cocaine seeking was also assessed.

Results

Intraperitoneal administration of NPSR-QA1 (15–30 mg/kg) did not affect cocaine self-administration. Conversely, NPSR-QA1 (15–30 mg/kg) decreased discriminative cue-induced cocaine relapse. At the lowest dose, this effect was specific, while at the highest dose, NPSR-QA1 also reduced food self-administration. The efficacy of NPSR antagonism on cocaine seeking was confirmed with [D-Cys(tBu)⁵]NPS (10–30 nmol/rat) as it markedly inhibited relapse behavior following site-specific injection into the lateral hypothalamus and the perifornical area of the hypothalamus but not into the central amygdala.

Conclusions

The identification of the NPS/NPSR system as an important new element involved in the physiopathology of cocaine addiction and the discovery of the anti-addictive properties of NPSR antagonists opens the possibility of exploring a new mechanism for cocaine addiction treatment.     

Effects of sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats

Rationale

Manipulations of nicotinic cholinergic receptors have been shown to influence both alcohol and nicotine intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes α4β2 nicotinic receptors with only modest receptor activation.

Objectives

The goal of the present study was to examine the effects of sazetidine-A on alcohol and nicotine self-administration in alcohol-preferring (P) rats.

Methods

P rats were given the choice of water or alcohol. Once stable baselines were established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.) and chronic (3 mg/kg for 10 days) effects of sazetidine-A on alcohol intake were assessed. Naltrexone (2.5 mg/kg) served as a positive control. The effect of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on saccharin (0.2%) preference was also assessed. In addition, the acute effects of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol intake after alcohol deprivation were evaluated. In another experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg) on IV nicotine self-administration in P and NP rats were assessed.

Results

Sazetidine-A caused a dose-dependent reduction in alcohol intake. Chronic sazetidine-A also effectively reduced alcohol intake until the seventh day of treatment, when partial tolerance appeared to develop. In the post-deprivation study, sazetidine-A significantly reduced alcohol intake and preference. Sazetidine-A at 3 mg/kg significantly reduced nicotine self-administration in both lines.

Conclusions

Sazetidine-A significantly reduced alcohol and nicotine intake in P rats that self-administer higher levels of both drugs. Sazetidine-A may hold promise for the treatment of alcohol and nicotine addiction.